Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

Dening, Yanina; Straßl, Theresa; Ruf, Viktoria; Dirscherl, Petra; Chovsepian, Alexandra; Stiévenard, Aliçia; Khairnar, Amit; Schmidt, Felix; Giesert, Florian; Herms, Jochen; Levin, Johannes; Dieterich, Marianne; Falkai, P.; Weisenhorn, Daniela M. Vogt; Wurst, Wolfgang; Giese, Armin; Pan‐Montojo, Francisco

doi:10.1038/s41598-022-25790-2

Cited by 4 publications

(2 citation statements)

References 54 publications

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“…In fact, αSyn aggregates spread between interconnected brain areas in a cell-to-cell and prion-like fashion which involve neurons and non-neuronal cells [58,59]. Transsynaptical transmission of aSyn may be triggered by the oligomeric aSyn-mediate microglia activation in the early phases of the disease [60] or by interactions between endogenous aSyn and mitochondria [61,62]. However, cells differentially mediate the uptake of the aSyn fibrils involving processes such as receptor-mediated endocytosis, extracellular vesicles and tunneling nanotubes.…”

Section: αSyn Toxicitymentioning

confidence: 99%

Alpha Synuclein Toxicity and Non-motor Parkinson’s

Mazzotta,

Conte

2024

Preprint

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Parkinson’s disease (PD) is a common multisystem neurodegenerative disorder affecting 1% of the population above 60 years. The main neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of alpha synuclein (Syn)-rich Lewy bodies both manifesting with classical motor signs. Syn has emerged as a key protein in PD pathology as it can spread through synaptic networks to reach several anatomical regions of the body contributing to the appearance of non-motor symptoms (NMS) considerate prevalent among individuals before PD diagnosis and persisting throughout the patient’s life. NMS mainly include loss of taste and smell, constipation, psychiatric disorders, dementia, rapid eye movement (REM) sleep behavior impairment, urogenital dysfunction, and cardiovascular impairment. This review summarizes the more recent findings showing the impact of Syn deposits on several prodromal NMS and emphasizes the importance of early detection of Syn toxic species in biofluids and peripheral biopsies as prospective biomarkers in PD.

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Section: αSyn Toxicitymentioning

confidence: 99%

Alpha Synuclein Toxicity and Non-motor Parkinson’s

Mazzotta,

Conte

2024

Preprint

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“…Once internalized by recipient cells, aSyn aggregates may induce the misfolding and aggregation of intracellular aSyn, thus perpetuating the cycle of aggregate formation (Masuda‐Suzukake et al, 2013; Paumier et al, 2015). Experiments using aSyn KO mice showed that endogenous aSyn is essential for the spreading of pathology, a process that does not require aSyn toxicity (Dening et al, 2022). Consequently, transmitting aSyn aggregates between cells may contribute to the progression of neurodegeneration observed in PD and related disorders.…”

Section: Introductionmentioning

confidence: 99%

PrP meets alpha‐synuclein: Molecular mechanisms and implications for disease

Vieira,

Barros,

Domingues

et al. 2023

Journal of Neurochemistry

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The discovery of prions has challenged dogmas and has revolutionized our understanding of protein‐misfolding diseases. The concept of self‐propagation via protein conformational changes, originally discovered for the prion protein (PrP), also applies to other proteins that exhibit similar behavior, such as alpha‐synuclein (aSyn), a central player in Parkinson's disease and in other synucleinopathies. aSyn pathology appears to spread from one cell to another during disease progression, and involves the misfolding and aggregation of aSyn. How the transfer of aSyn between cells occurs is still being studied, but one important hypothesis involves receptor‐mediated transport. Interestingly, recent studies indicate that the cellular prion protein (PrPC) may play a crucial role in this process. PrPC has been shown to act as a receptor/sensor for protein aggregates in different neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Here, we provide a comprehensive overview of the current state of knowledge regarding the interaction between aSyn and PrPC and discuss its role in synucleinopathies. We examine the properties of PrP and aSyn, including their structure, function, and aggregation. Additionally, we discuss the current understanding of PrPC's role as a receptor/sensor for aSyn aggregates and identify remaining unanswered questions in this area of research. Ultimately, we posit that exploring the interaction between aSyn and PrPC may offer potential treatment options for synucleinopathies.image

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The Synucleins and the Astrocyte

Myers

Brahimi

Jenkins

et al. 2023

Biology

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Synucleins consist of three proteins exclusively expressed in vertebrates. α-Synuclein (αS) has been identified as the main proteinaceous aggregate in Lewy bodies, a pathological hallmark of many neurodegenerative diseases. Less is understood about β-synuclein (βS) and γ-synuclein (γS), although it is known βS can interact with αS in vivo to inhibit aggregation. Likewise, both γS and βS can inhibit αS’s propensity to aggregate in vitro. In the central nervous system, βS and αS, and to a lesser extent γS, are highly expressed in the neural presynaptic terminal, although they are not strictly located there, and emerging data have shown a more complex expression profile. Synapse loss and astrocyte atrophy are early aspects of degenerative diseases of the brain and correlate with disease progression. Synucleins appear to be involved in synaptic transmission, and astrocytes coordinate and organize synaptic function, with excess αS degraded by astrocytes and microglia adjacent to the synapse. βS and γS have also been observed in the astrocyte and may provide beneficial roles. The astrocytic responsibility for degradation of αS as well as emerging evidence on possible astrocytic functions of βS and γS, warrant closer inspection on astrocyte–synuclein interactions at the synapse.

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Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

Cited by 4 publications

References 54 publications

Alpha Synuclein Toxicity and Non-motor Parkinson’s

Alpha Synuclein Toxicity and Non-motor Parkinson’s

PrP meets alpha‐synuclein: Molecular mechanisms and implications for disease

The Synucleins and the Astrocyte

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